1. Field of the Invention
The present invention pertains to the field of oxinates and, particularly, to the therapeutic use of metal chelated 8-hydroxyquinolinates in the treatment of cancers, precancerous lesions, and other abnormal tissues.
2. Statement of the Problem
A preferred treatment modality for many cancers is surgical excision of the cancerous lesion. Surgical excision is not always desirable when surgery could sever nerves or produce scars that interfere with normal movements in tissues proximate the site of surgery.
Chemicals have been developed to treat cancers. Rate-sensitive cytotoxic drugs have cytotoxic effects on all tissue types, but are particularly effective against certain cancers that function at a metabolic rate greater than the metabolic rate of normal cells. The increased metabolic rate of these cancers makes them more susceptible to the cytotoxicity of the drugs. In this manner it is possible to provide a dosage that is fatal to cancer cells, while that same dosage is not fatal to normal cells. By way of example, U.S. Pat. No. 5,684,169 teaches the formation of cyclodextrin complexes of taxol to improve the solubility of taxol in water. Taxol is a cytotoxic drug that is believed to attack and kill cancer cells with a rate-sensitive effect.
Other chemicals are specifically designed for the treatment of skin cancers and cancers that reside close to the skin. U.S. Pat. No. 5,605,700 describes a transdermal preparation containing toremifene for use in treating cancers of the skin or cancers that reside a short distance from the skin, such as metastic lesions of breast cancer. The transdermal preparations are said to be of particular interest in the treatment of melanoma, lymphoma, Kaposi""s sarcoma, and fungoides mycosis. Escharotics or caustic chemicals, such as Podophylin or tricholoroacetic acid which are used in the treatment of skin cancer, venereal warts and human papilloma virus, are designed to produce a chemical burn that destroys substantially all of the tissues in contact with the chemical. None of these chemicals is selective in destroying only the lesion while leaving behind healthy tissues that exist close to the site of the lesion, i.e., the chemicals lack selectivity and specificity.
The chemical 8-hydroxyquinoline is not used for the treatment of epithelial 5 lesions, such as epitheliomas and venereal warts. 8-hydroxyquinoline is known by various other names including oxyquinoline, oxine, 8-hydroxy-chinolin, hydroxybenzopyridine, and 8-oxyquiniline. The federal government has approved 8-hydroxyquinoline for cosmetic use in low concentrations of less than five percent. At these concentrations, 8-hydroxyquinoline functions as a cosmetic biocide, as reported in JACT 11(4), 1992. U.S. Pat. No. 4,302,467 reports the use of 8-hydroxyquinoline or its chelates in combination with dehydroacetic acid or sorbic acid. The combination is reported to work synergistically against bacteria and fungus. According to the Merck Index 11th Edition, Merck and Co. publ., p.4779. (1989), 8-hydroxyquinoline is used as a fungistat, a chelating agent in the determination of trace metals, and a disinfectant.
Chapter ten of the book Albert, Selective Toxicity 3rd Ed., New York, John Wiley and Sons, Inc. (1965) states on page 370-378 that the antibacterial action of oxine is due to chelation. Iron-chelated forms of oxine are toxic to gram-positive bacteria when mixed with Fe3+ at a 1:1 molar ratio and a 1:2 molar ratio of oxine to iron, but toxicity diminishes at a 1:3 ratio. Despite its strong antibacteriological effects, oxine and its derivatives are not normally injected into the bloodstream because they are inactivated by red blood cells, which secrete a substance that binds oxine.
There remains a need for a topically applied therapeutic composition with selective toxicity in the treatment of epithelial lesions.
The present invention overcomes the problems that are outlined above by providing a topically applied therapeutic composition having selective toxicity in the treatment of epithelial lesions. The therapeutic composition demonstrates selective toxicity on human lung cancer, breast cancer, and melanoma. Furthermore, the composition has been used to treat human patients where it demonstrates a one-hundred percent therapeutic index with selective toxicity against venereal warts, male veruoca warts, lesions produced by human papilloma virus, basal cell carcinoma, solar keratosis, and Kaposi""s sarcoma. In veterinary applications where dogs, cats, and horses are the patients, the composition shows a one-hundred percent therapeutic index with selective toxicity against eye cancer, sarcoids, sarcoma, malignant melanoma, rectal adenoma, histiocytoma, and sebaceous adenoma. In this context, the therapeutic index is defined as the number of patients cured divided by the number of patients treated. While chemical excision of these lesions is accomplished, the composition is essentially without escharotic effects on healthy tissue.
A therapeutic composition according to the present invention contains 8-hydroxyquinoline or a functional homologue thereof, a metal chelating agent, and a carrier. The 8-hydroxyquinoline and the metal chelating agent are present in effective amounts for treating mammalian epithelial lesions selected from the group consisting of cancerous lesions, precancerous lesions, and warts. These mammalian epithelial lesions specifically include venereal warts, male veruoca warts, lesions produced by human papilloma virus, basal cell carcinoma, solar keratosis, Kaposi""s sarcoma, eye cancer, sarcoids, sarcoma, malignant melanoma, rectal adenoma, histiocytoma, and sebaceous adenoma.
In veterinary applications, solutions according to the present invention have been used with success to treat dermal lesions including acanthosis nigricans, acne, acral lick dermatitis, allergic reactions, calcinosis circumscripta, calcinosis cutis, cutaneous asthenia, deep mycotic infection, demodicosis, acute and chronic dermatitis, dermatomycosis, eosinophillic granuloma complex, epidermal cysts, hypothyroidism, ichthyosis, insect bites, lentigo, nodular penniculitis, pemphigus, canine scabies, and thallium toxicosis. The solutions have also been used with success to treat veterinary tumors including basal cell tumors, fibroma, fibrosarcoma, granuloma, hemangioma, hemangiopericytioma, histiocytoma, intracuaneous cornyfying epithelioma, lipoma, lymphosarcoma, mast cell tumor, melanoma, papilloma, periana adenoma, reticulum cell sarcvoma, sebaceouos gland tumor, squamous cell carcinoma, sweat gland (apocrine) tumor, and transmissible venereal tumor. Injectable forms of the solutions have been used to counteract the effects of bites from the brown recluse spider, which can have disfiguring and painful consequences if left untreated.
Therapeutically effective amounts include therapeutically effective concentrations, as well as therapeutically effective ratios of the 8-hydroxyquinoline and the metal chelating agent. The preferred range for therapeutically effective ratio is one wherein the molar ratio of 8-hydroxyquinoline to the metal chelating agent ranges from 1:1 up to 1:N, where N is the oxidation state of the metal chelating agent. At the ratio of 1:N, the chelated oxine is easily transported across the cell membrane because it has a neutral charge. Charged species are also observed to be threrapeutically effective. Where the metal has a valence of +2, therapeutically effective ratios range from 1:1 to 1:3, and the most preferred ratio is about 1:2. The 8-hydroxyquinoline is preferably present in an amount ranging from five percent to twenty percent of the composition by weight, and the most preferred amount of 8-hydroxyquinoline is about ten percent by weight. More or less 8-hydroxyquinoline may be used. For example, injectable forms or orally consumed forms may have reduced concentrations for long term uses, such as one half percent to five percent concentrations of chelated 8-hydroxyquinoline to be used as continuing maintenance treatments for a cancer patient who is in remission but remains at risk for a recurrence of cancer. The amount of 8-hydroxyquinoline may be increased beyond about twenty percent by weight, but these higher concentrations, in combination with zinc chloride chelating agent, are likely to induce a sensitized reaction in the patient. Use of these higher concentrations may be justified when faced with a tumor or lesion that is particularly difficult to remove.
As stated above, the therapeutic compositions include a metal chelating agent. This agent is preferably a chelatable metal bonded to a halogen, which yields an ionic species of the metal in solution. This reaction is free for covalent and coordinate bonding with oxine in solution. The metal is preferably a heavy metal or a transition metal. Heavy metals are more preferred, and the preferred heavy metals are copper, iron, manganese, molybdenum, and cobalt. Zinc is the most preferred heavy metal. The metal is preferably provided as a salt including a metal and a halogen, though the halogen is not necessarily required for purposes of the invention. The halogen may be involved in the mechanism of transport across the cell membrane. Chlorine is the most preferred halogen. Thus, the most referred metal chelating agent is provided as zinc chloride.
The carrier is preferably formed of a gel base to enhance the time during which the composition is retained on the epithelial lesion where it is applied. Lecithin is preferably added as a penetrating agent, and the penetrating effect of lecithin may be enhanced by the use of dimethyl sulfoxide (DMSO). The carrier also contains an emollient, such as isopropyl palmitate or isopropyl myristate. The gel base is made of a hydrophilic polymer, such as polyacrylamide or polyoxyalkylene derivatives of propylene glycol. Other hydrophilic gels may also be used, e.g., hydrophilic petrolatum bases. A topical steroid, such as 0.5% hydrocortizone may be added to decrease the incidence or severity of contact dermatitis proximate the site of topical application. Humectants, such as propylene glycol may be added to reduce dryness of the lesion during the course of treatment. Glycols are also useful as additives to enhance the flow characteristics of the chelated compositions, and as carries in inhalants according to the invention.
A further preferred aspect of the invention is the use of antioxidants to stabilize chelated 8-hydroxyquinoline in vivo. Nordihydroguiaretic acid, derivatives of nordihydroguiaretic acid, and functional homologues of nordihydroguiaretic acid stabilize zinc-chelated 8-hydroxyquinoline against inactivation by thermolabile substances in the blood for solutions that are injected into the body. Similarly, 8-hydroxyquinoline and zinc chloride coprecipitated with sodium ascorbate forms a stable orally administrable product having therapeutic efficacy.
The composition is administered to the epithelial lesion by topical application, injection, or oral administration. Where the lesion is scarred or thickening is observed, topical efficacy is enhanced by scraping and perforating the lesion with a needle or scalpel prior to topical application of the ointment, in order to enhance the penetration of the ointment into the lesion. Only one topical application is typically required, and the tissue forming the lesion is expected to turn black and necrotic after about two to four weeks. The dead tissue is peeled away, and the wound site typically heals to completion after another three to four weeks have passed. Even where large lesions have been removed in this manner, there is typically no scarring, and even the hair follicles are restored to full function. Additional amounts of ointment may be applied if tumor necrosis is not proceeding quickly enough. Additional solution is preferably applied to the wound margins after the removal of necrotic tissue to assure that all of the cancer cells have been eliminated.